This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

SummarySensory systems are known to adapt their coding strategies to the statistics of their environment, but little is still known about the perceptual implications of such adjustments. We investigated how auditory spatial processing adapts to stimulus statistics by presenting human listeners and anesthetized ferrets with noise sequences in which interaural level differences (ILD) rapidly fluctuated according to a Gaussian distribution. The mean of the distribution biased the perceived laterality of a subsequent stimulus, whereas the distribution's variance changed the listeners' spatial sensitivity. The responses of neurons in the inferior colliculus changed in line with these perceptual phenomena. Their ILD preference adjusted to match the stimulus distribution mean, resulting in large shifts in rate-ILD functions, while their gain adapted to the stimulus variance, producing pronounced changes in neural sensitivity. Our findings suggest that processing of auditory space is geared toward emphasizing relative spatial differences rather than the accurate representation of absolute position.

No abstract

Currently available screening tests do not deliver the required sensitivity and specificity for accurate diagnosis of ovarian or endometrial cancer. Infrared (IR) spectroscopy of blood plasma or serum is a rapid, versatile, and relatively non-invasive approach which could characterize biomolecular alterations due to cancer and has potential to be utilized as a screening or diagnostic tool. In the past, no such approach has been investigated for its applicability in screening and/or diagnosis of gynaecological cancers. We set out to determine whether attenuated total reflection Fourier-transform IR (ATR-FTIR) spectroscopy coupled with a proposed classification machine could be applied to IR spectra obtained from plasma and serum for accurate class prediction (cancer vs. normal). Plasma and serum samples were obtained from ovarian cancer cases (n = 30), endometrial cancer cases (n = 30) and non-cancer controls (n = 30), and subjected to ATR-FTIR spectroscopy. Four derived datasets were processed to estimate the real-world diagnosis of ovarian and endometrial cancer. Classification results for ovarian cancer were remarkable (up to 96.7%), whereas endometrial cancer was classified with a relatively high accuracy (up to 81.7%). The results from different combinations of feature extraction and classification methods, and also classifier ensembles, were compared. No single classification system performed best for all different datasets. This demonstrates the need for a framework that can accommodate a diverse set of analytical methods in order to be adaptable to different datasets. This pilot study suggests that ATR-FTIR spectroscopy of blood is a robust tool for accurate diagnosis, and carries the potential to be utilized as a screening test for ovarian cancer in primary care settings. The proposed classification machine is a powerful tool which could be applied to classify the vibrational spectroscopy data of different biological systems (e.g., tissue, urine, saliva), with their potential application in clinical practice.

Clinical practice guidelines are now ubiquitous. This article describes the emergence of such guidelines in a way that differs from the two dominant explanations, one focusing on administrative cost-cutting and the other on the need to protect collective professional autonomy. Instead, this article argues that the spread of guidelines represents a new regulation of medical care resulting from a confluence of circumstances that mobilized many different groups. Although the regulation of quality has traditionally been based on the standardization of professional credentials, since the 1960s it has intensified and been supplemented by efforts to standardize the use of medical procedures. This shift is related to the spread of standardization within medicine and especially in research, public health, and large bureaucratic health care organizations.

SummaryMalignant tumor cells can escape CD8 + cytotoxic T cell killing by downregulating class I major histocompatibility complex (MHC) expression. Stable class I MHC surface expression requires loading of the heavy chain/light chain dimer with antigenic peptide, which is delivered to class I MHC molecules in the endoplasmic reticulum by the presumed peptide transporter, encoded by the transporter associated with antigen presentation (TAP) 1 and 2 genes. We have investigated whether loss of class I MHC expression frequently observed in different cancers could result from interference with TAP function. A polyclonal antiserum, raised against a bacterial glutathione S-transferase/human TAP-1 fusion protein, was used for the immunohistochemical analysis of TAP-1 expression in 76 cervical carcinomas. Results showed loss of TAP-1 expression in neoplastic cells in 37 out of 76 carcinomas. Immunohistochemical double staining procedures in combination with HLA-specific antibodies revealed congruent loss at the single cell level of TAP-1 and HLA-A/B expression in 28 out of 37 carcinomas. The remaining samples expressed HLA(-A) in the absence of TAP-1 (n = 6) or showed loss of HLA(-A/B) while TAP-1 was expressed (n = 3). These data strongly indicate that inhibition of peptide transport by downregulation of TAP-1 is a potential strategy of malignant cells to evade immune surveillance.T he transporter associated with antigen presentation (TAP) is encoded by the TAP-I and -2 genes (1, 2), located within the class II MHC region. Their products share structural properties with members of the superfamily of ATP-binding transporters (2, 3) and their function is to translocate antigenic peptide from the cytosol into the endoplasmic reticulum (Elk). There, class I H chain, L chain (B2-microglobulin), and peptide assemble into a complex which is then transported to the cell surface. Mutant cell lines (4, 5) or mice (6) lacking TAP-1 and/or -2 genes do not present antigen to CD8 + Tcells and show strongly reduced levels of surface class I MHC molecules, indicating that peptide should be considered the essential third subunit of the class I complex (7-9). Upon viral infection or malignant cell transformation, the ensuing alternations in gene expression result in the generation of novel sets of peptides available for binding to class I MHC products. These are potential targets for CD8 + CTLs Besides deprivation of H and/or L chains, the loss of peptide could also result in reduced class I MHC surface expression. Downregulation of class I MHC expression has been found in a substantial number of cervical carcinomas, containing human papilloma-virus type 16 DNA (21,22 that show loss of class I MHC surface expression, a posttranscriptional regulation has been postulated (23). Loss of TAP function and the consequent failure to produce stable class I MHC molecules could be an explanation. Therefore in this study, class I MHC and TAP-1 expression were examined in 76 carcinomas of the uterine cervix by immunohistochemistry with class I H chai...

SummaryBackgroundNeural systems must weight and integrate different sensory cues in order to make decisions. However, environmental conditions often change over time, altering the reliability of different cues and therefore the optimal way for combining them. To explore how cue integration develops in dynamic environments, we examined the effects on auditory spatial processing of rearing ferrets with localization cues that were modified via a unilateral earplug, interspersed with brief periods of normal hearing.ResultsIn contrast with control animals, which rely primarily on timing and intensity differences between their two ears to localize sound sources, the juvenile-plugged ferrets developed the ability to localize sounds accurately by relying more on the unchanged spectral localization cues provided by the single normal ear. This adaptive process was paralleled by changes in neuronal responses in the primary auditory cortex, which became relatively more sensitive to these monaural spatial cues. Our behavioral and physiological data demonstrated, however, that the reweighting of different spatial cues disappeared as soon as normal hearing was experienced, showing for the first time that this type of plasticity can be context specific.ConclusionsThese results show that developmental changes can be selectively expressed in response to specific acoustic conditions. In this way, the auditory system can develop and simultaneously maintain two distinct models of auditory space and switch between these models depending on the prevailing sensory context. This ability is likely to be critical for maintaining accurate perception in dynamic environments and may point toward novel therapeutic strategies for individuals who experience sensory deficits during development.

HLA-restricted cytotoxic T-lymphocyte (CTL) recognition of human papillomavirus (HPV) oncogene products may be important in the control of the HPV infections associated with the development of cervical cancer. We have identified, in HLA-B7 individuals, a consistent variation in the HPV16 E6 oncoprotein sequence, which alters an HLA-B7 peptide binding epitope in a way likely to influence immune recognition by CTLs. These results illustrate a biologically relevant mechanism for escape from immune surveillance of HPV16 in HLA-B7 individuals. Thus, both HLA type and HPV16 strain variation need to be considered in the screening of at-risk individuals and for the rational design of anti-HPV vaccines.